Fig. 1: Phenotypic and dysmorphic features of patient 1 (A and B),...

Human Genetics: Concepts And Application

Because of natural selection, different alleles are more likely to confer a survival advantage in different environments. Cycles of infectious disease prevalence and virulence often reflect natural selection.

Balanced PolymorphismIf natural selection eliminates individuals with detrimental phenotypes from a population, then why do harmful mutant alleles persist in a gene pool? A disease can remain prevalent when heterozygotes have some other advantage over individuals who have two copies of the wild type allele. When carriers have advantages that allow a detrimental allele to persist in a population, balanced polymorphism is at work. This form of polymorphism often entails heterozygosity for an inherited illness that protects against an infectious illness. Examples are fascinating.

Sickle Cell DiseaseSickle Cell disease is an autosomal recessive disorder that causes anemia, joint pain, a swollen spleen, and frequent, severe infections. It illustrates balanced polymorphism because carriers are resistant to malaria, an infection by the parasite Plasmodium falciparum that causes cycles of chills and fever. The parasite spends the first stage of its life cycle in the salivary glands of the mosquito Anopheles gambiae. When an infected mosquito bites a human, the malaria parasite enters the red blood cells, which transport it to the liver. The red blood cells burst, releasing the parasite throughout the body.

In 1949, British geneticist Anthony Allison found that the frequency of sickle cell carriers in tropical Africa was higher in regions where malaria raged all year long. Blood tests from children hospitalized with malaria found that nearly all were homozygous for the wild type of sickle cell allele. The few sickle cell carriers among them had the mildest cases of malaria. Was the presence of malaria somehow selecting for the sickle cell allele by felling people who did not inherit it? The fact that sickle cell disease is far less common in the United States, where malaria is rare, supports the idea that sickle cell heterozygosity provides a protective effect.

Further evidence of a sickle cell carrier's advantage in a malaria-ridden environment is the fact that the rise of sickle cell disease parallels the cultivation of crops that provide breeding grounds for Anopheles mosquitoes. About 1,000 B.C., Malayo-Polynesian sailors from southeast Asia traveled in canoes to East Africa, bringing new crops of bananas, yams, taros, and coconuts. When the jungle was cleared to grow these crops, the open space provided breeding ground for mosquitoes. The insects, in turn, offered a habitat for part of the life cycle of the malaria parasite.

The sickle cell gene may have been brought to Africa by people migrating from Southern Arabia and India, or it may have arisen by mutation directly in East Africa. However it happened, people who inherited one copy of the sickle cell allele had red blood cell membranes that did not admit the parasite. Carriers had more children and passed the protective allele to approximately half of them. Gradually, the frequency of the sickle cell allele in East Africa rose from 0.1 percent to a spectacular 45 percent in thirty-five generations. Carriers paid the price for this genetic protection, whenever two produced a child with sickle cell disease.

A cycle set in. Settlements with large numbers of sickle cell carriers escaped debilitating malaria. They were therefore strong enough to clear even more land to grow food- and support the disease-bearing mosquitoes. Even today, sickle cell disease is more prevalent in agricultural societies than among people who hunt and gather their food.

Glucose-6-Phosphate Dehydrogenase DeficiencyG6PD deficiency is a sex-linked enzyme deficiency that affects 400 million people worldwide. It causes life-threatening hemolytic anemia, in which red blood cells burst. However, it develops only under specific conditions- eating fava beans, inhaling certain types of pollen, taking certain drugs, or contracting certain infections. Studies on African children with severe malaria show that heterozygous females and hemizygous males for G6PD deficiency are underrepresented. This suggests that inheriting the enzyme deficiency gene somehow protects against malaria.

The fact that G6PD deficiency is sex-linked introduces a possibility we do not see with sickle cell disease, which is autosomal recessive. Because both heterozygotes and hemizygotes are selected for, the mutant allele should eventually predominate in a malaria-exposed population. However, this doesn't happen- there are still males hemizygous and females homozygous for the wild type allele. The reason again relates to natural selection. People with the enzyme deficiency- hemizygous males and homozygous females- are selected out of the population by the anemia. Therefore, natural selection acts in two directions on the hemizygous males- selecting for the mutant allele because it protects against malarial infection, yet selecting against it because an enzyme deficiency. This is the essence of balanced polymorphism.

PKUPhenylketnonuria is an inborn error of metabolism in which a missing enzyme causes the amino acid phenylalanine to build up, with devastating effects on the nervous system unless the individual follows a restrictive diet. Carriers of this autosomal recessive condition have elevated phenylalanine levels- levels that are not sufficiently high to cause symptoms, but that are high enough that they may have a protective effect during pregnancy. Physicians have observed that women who are PKU carriers have a much lower-than�average incidence of miscarriage. One theory is that excess phenylalanine somehow inactivates a poison, called ochratoxin A, that certain fungi produce and that is known to cause spontaneous abortion.

History provides the evidence that links PKU heterozygosity to protection against a fungal toxin. PKU is most common in Ireland and western Scotland, and many affected families living elsewhere trace their roots to this part of the world. If PKU carriers were most likely to have children than non-carriers because of the protective effects of the PKU gene, over time, the disease-causing allele would increase the population.

Tay-Sachs DiseaseCarrying Tay-Sachs disease may protect against tuberculosis (TB). In Ashkenazim populations, up to 11 percent of the people are Tay-Sachs carriers. During World War II, TB ran rampant in Eastern European Jewish settlements. Often, healthy relatives of children with Tay-Sachs disease did not contact TB, even when repeatedly exposed. The protection against TB that Tay-Sachs disease heterozygosity apparently offered remained among the Jewish people because they were prevented from leaving the ghettos. The mutant allele increased in frequency as TB selectively felled those who did not carry it and the carriers had children with each other. Genetic drift may also have helped isolate the Tay-Sachs allele, by chance, in groups of holocaust survivors. Precisely how lowered levels of the gene product, an enzyme called hexoseaminidase A, protect against TB isn't known.

Cystic FibrosisBalanced polymorphism may explain why cystic fibrosis is so common- the anatomical defect that underlies CF protects against diarrheal illnesses, such as cholera.

Cholera epidemics have left their mark on human populations, causing widespread death in just days. In the summer of 1831, an epidemic killed 10 percent of the population of St. Louis, and in 1991, an epidemic swept Peru. Cholera bacteria causes diarrhea, which rapidly dehydrates the body and can lead to shock and kidney and heart failure. The bacterium produces a toxin that opens chloride channels in the small intestine. As salt (NaCl) leaves the cells, water follows, in a natural chemical tendency to dilute the salt. Water rushing out of intestinal cells leaves the body as diarrhea.

In 1989, when geneticists identified the CF gene and described its protein product as a regulator of a chloride channel in certain secretory cells, a possible explanation for the prevalence of the inherited disorder emerged. Cholera opens chloride channels, letting chloride and water leave cells. The CFTR protein does just the opposite, closing chloride channels and trapping salt and water in cells, which dries out mucus and other secretions. A person with CF cannot contract cholera, because the toxin cannot open the chloride channels in the small intestine.

Carriers of CF enjoy the mixed blessing of a balanced polymorphism. They do not have enough abnormal chloride channels to cause the labored breathing and clogged pancreas of cystic fibrosis, but they do have enough of a defect to prevent the cholera from taking hold. During the devastating cholera epidemics that have peppered history, individuals carrying mutant CF alleles had a selective advantage, and they disproportionately transmitted those alleles to future generations. However, because CF arose in Western Europe and cholera in Africa, perhaps an initial increase in CF herterozygosity was a response to a different diarrheal infection.

Tay-Sachs Disease

Glossary Definition: Tay-Sachs Disease

Tay-Sachs disease results in the deterioration of the nervous system, usually resulting in death before the patient reaches age 5. It is caused by the absence of an enzyme which breaks down lipids, resulting in a lethal accumulation in cells. There is no treatment, but potential parents can be identified as carriers for the disease with a blood test.

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Tay-Sachs And Rare Disease Registries – The Health Heroes Podcast

Episode four of Kantar Health's Health Heroes podcast tackles pharma's rare disease challenges, the role of patient registries and hears a moving story about the rare genetic disorder Tay-Sachs disease.

Joining me for this instalment of Health Heroes are Geneviève Bonnélye-Fesnien, global head of real-world evidence, research and consulting at Kantar Health, and Dan Lewi, co-founder of The Cure & Action for Tay-Sachs (or CATS) Foundation.

Dan's eldest daughter Amelie was diagnosed with Tay-Sachs in 2011 at 15 months of age and he shares the emotional story of caring for her and how that led to setting up The CATS Foundation.

This episode of the podcast also looks at the GM2 Disease Registry, managed by The CATS Foundation with support from Kantar Health, and how it will help both patients and the pharma companies working on treatments for them.

The podcast finishes up with an overview from Geneviève on the current outlook for rare diseases.

The Health Heroes podcast series aims to inform and educate life sciences companies on ways for getting closer to patients to help drive improved health outcomes.

Previous episodes have covered the impact of a rare disease, learning from China's COVID-19 experience and the coronavirus pandemic's effect on mental health in the US.

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